Assessment of Favipiravir and Remdesivir in Combination for SARS-CoV-2 Infection in Syrian Golden Hamsters

Abstract

Favipiravir (FVP) and remdesivir (RDV) have demonstrable antiviral activity against SARS-CoV-2. Here, the efficacy of FVP, RDV, and FVP with RDV (FVP + RDV) in combination was assessed in Syrian golden hamsters challenged with SARS-CoV- 2 (B.1.1.7) following intraperitoneal administration. At day 4 post infection, viral RNA and viral antigen expression were significantly lower in lungs for all three treatment groups compared to the sham treatment. Similarly, viral titres in the lungs were lower in all treatment groups compared to the sham treatment. The FVP + RDV combination was the only treatment group where viral RNA in nasal turbinate and lung, virus titres in lung, and viral antigen expression (lung) were all lower than those for the sham treatment group. Moreover, lower viral titre values were observed in the FVP + RDV group compared to other treatment groups, albeit only significantly lower in comparison to those in the RDV-only-treated group. Further assessment of the potential utility of FVP in combination with RDV may be warranted. Future studies should also consider whether the combination of these two drugs may reduce the speed at which drug resistance mutations are selected.

Keywords: SARS-CoV-2; combination therapy; favipiravir; remdesivir.

Figure 1

Percentage weight change of each treatment group throughout the entire study duration. Hamsters in each treatment group (n = 4) were weighed every day from day −1 to day 4. Weights are represented as a percentage of the initial weight measured at the beginning of the study, on day −1. (A) Sham treatment vs FVP, (B) sham treatment vs RDV, (C) sham treatment vs FVP + RDV, and (D) FVP vs. RDV vs. FVP + RDV. Two-way ANOVA multiple comparison with Bonferroni correction was used to determine statistical significance. * = p ≤ 0.05, ** = p ≤ 0.01, *** = p ≤ 0.001, **** = p ≤ 0.0001. Dotted lines represent standard deviations.

Figure 2

Viral quantification (N-RNA) and lung viral titres (PFU/µg of protein) of SARS-CoV-2 from samples of each treatment group (n = 4) at day 4. (A) Nasal turbinate and (B) lung copies of viral N-RNA/µg of RNA, relative to 18S, from each treatment group. Statistical significance between the sham treatment group and treated groups was determined using a nonparametric Mann–Whitney test (one-tailed, p ≤ 0.05). (C) Sham treatment group samples were processed separately from the treatment groups (hence no statistical comparison could be performed). Statistical significance between the different treatment groups (FVP vs. RDV, FVP vs. FVP + RDV, and RDV vs. FVP + RDV) was determined using a nonparametric Mann–Whitney test (one-tailed, p ≤ 0.05). Lung viral titres from the FVP + RDV combination group were lower in comparison to the FVP and RDV monotherapy groups but only significantly different from the latter. ns = not statistically significant, * = p ≤ 0.05. LOD: limit of detection (indicated by dotted line).

Figure 3

Morphometric analysis to compare the extent of viral antigen expression in the different treatment groups. (A) The extent of viral antigen expression is determined as percentage area of viral nucleocapsid protein (NP) expression in the area covered by the lung section. Statistical significance between the sham treatment group (n = 4) and the corresponding treated group (n = 4) was determined using an unpaired t-test (two-tailed, p ≤ 0.05). ** = p ≤ 0.01. (B) Correlation of viral N-RNA levels (as copies of N-RNA/µg of RNA, relative to 18S) and the extent of viral NP expression (as percentage area of viral antigen in the lung section).